期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 214, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113244
关键词
RNA polymerase II; CDK9 inhibitor; Apoptosis; Mcl-1; Chronic lymphocytic leukaemia; Anti-Cancer agents
资金
- Cancer Research UK [C21568/A8988, C21568/A12474]
CDK9 is a crucial cyclin-dependent kinase involved in cell cycle and transcription regulation. The optimization of pyrimidine compounds as CDK9 inhibitors, particularly compound 30m, has shown significant selectivity and broad anti-proliferative activities. This research provides promising insights into potential treatments for various diseases involving CDK9 dysregulation.
Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells. (C) 2021 Elsevier Masson SAS. All rights reserved.
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